#AAN2018 — Type 1 SMA Babies Treated with AVXS-101 Achieving New Milestones, Trials Show

Type 1 spinal muscular atrophy (SMA) babies treated with AveXis’ gene therapy candidate AVXS-101 continue to achieve unprecedented motor milestones and do not require breathing or nutritional support, according to recent data from the company.

AveXis presented updated results from Phase 3 and Phase 1 trials at the 2018 American Academy of Neurology (AAN) Annual Meeting, taking place through April 27 in Los Angeles.

AVXS-101 contains a normal version of the SMN gene, which is defective in SMA. The lower levels of the SMN protein cause the loss of specialized nerve cells called motor neurons, ultimately leading to progressive muscle weakness and atrophy.

Type 1 SMA is the most severe and most common type of spinal muscular atrophy. Symptoms appear between birth and 6 months of age, and are characterized by serious muscle weakness, including an inability to raise the head to breathe, cough or swallow normally. Children with type 1 SMA can only sit upright with support.

The STR1VE Phase 3 trial (NCT03306277) is assessing the effectiveness and safety of a one-time intravenous  infusion of AVXS-101 in type 1 SMA children younger than 6 months.

The multicenter, open-label, one-time-dose study is enrolling up to 15 children with SMN1 mutations and one to two copies of the SMN2 gene, which although able to generate the SMN protein, does so in an unstable manner and in a shorter-than-normal version. The severity of the disease correlates with the number of SMN2 gene copies: The more copies a patient has, the less severe the disease will be.

The trial’s main objectives are achievement of independent sitting for 30 seconds at 18 months of age and survival without the need for permanent ventilation at 14 months old.

The study, “Gene Replacement Therapy for SMA Type 1: Pivotal Study (STR1VE) Update,” presented April 25 as a scientific poster during the AAN meeting’s Emerging Science Poster Presentations, reported initial results of the STR1VE trial.

As of April 11, 11 type 1 SMA patients with two SMN2 copies were recruited for the trial. The first three patients were dosed at four-week intervals to allow for data analysis before dosing the next child.

The six patients who were at least one month post-treatment were all alive and event-free as of April 11. Mean age at dosing was 3.2 months, with the oldest patient being 5 months old. Results indicated that AVXS-101 was safe and well-tolerated. Four patients exhibited asymptomatic increases in serum aminotransferase level — possibly indicating liver disease or damage — which were lowered by prednisolone, a corticosteroid. No serious adverse events were reported.

Mean scores of CHOP-INTEND, an assessment of movement ability, increased by an average of 7.8 one month after dosing in six patients and 17.3 at three months in three patients. These results correlate to those of AveXis’ Phase 1 trial (NCT02122952), where children receiving the proposed therapeutic dose — 1.1 x 10¹⁴ vector genomes per kilogram — had increases of 9.8 points at one month and 15.4 points at three months.

No patients required ventilatory or nutritional support.

Follow-up data from Phase 1 trial in SMA Type 1

AveXis also presented 24-month follow-up data of this Phase 1 trial, which evaluated AVXS-101’s safety and tolerability in 15 type 1 SMA infants, enrolled before they were 6 months of age.

Earlier data had shown that 100% of treated children survived at 13.6 and 20 months of age, compared with the natural history in type 1 babies, which indicates that only 25% of children survive event-free at 13.6 months. This percentage goes down to 8% at 20 months.

These results, which were discussed in a recent interview with SMA News Today, included other unheard-of improvements, especially in the 12 children who received the higher dose (cohort 2), such as an ability to sit 30 seconds or longer unassisted, to roll over, and in some cases, to walk. Improved motor control was also observed in babies receiving the low dose.

“With a population closely matched to the Phase 1 trial, preliminary safety data and the early and rapid increases in CHOP-INTEND scores achieved by infants in this pivotal STR1VE trial are consistent with results of the Phase 1 trial of AVXS-101 in SMA Type 1,” John W. Day, MD, PhD, director of the Stanford Neuromuscular Program at Stanford University Medical Center, said in a press release.

Now, at 24 months post-treatment, AVXS-101 was shown to improve type 1 SMA patients’ survival and motor function.

All 15 patients were alive and did not require permanent ventilation. Mean age at the last follow-up was 27.8 months for children receiving the higher dose and 30.7 months for those in the lower dose group. AVXS-101 continued to show a positive safety profile, and no new treatment-related safety or tolerability concerns were identified.

Importantly, two more children were able to sit unassisted for 30 seconds or more, with a total of 11 out of 12 (92%) reaching this key milestone.

The study, “AVXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Continued Event Free Survival and Achievement of Developmental Milestones,” also presented at the AAN meeting, showed that 11 patients achieved head control, while two stood and walked independently.

Another study presented at the meeting, “AVXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Patients Treated Early with the Proposed Therapeutic Dose Were Able to Sit Unassisted at a Younger Age,” reported that 11 out of 12 patients achieved CHOP-INTEND scores equal to or greater than 40, and 10 achieved scores of 50 or higher, “both significantly superior to the published natural history,” the researchers wrote.

“The majority of Cohort 2 patients achieved sitting unassisted regardless of age at dosing; however, those dosed early achieved this milestone more quickly, emphasizing the need for newborn screening for SMA,” they said.

Importantly, the authors noted that additional children have achieved sitting unassisted since Jan. 20, 2017.

However, researchers showed concern that although CHOP-INTEND reliably detects early treatment impact, the upper range in its scale “appears to be insensitive to motor milestone achievement that was previously unanticipated.”

The study, “AVXS-101 Trial Experience: CHOP-INTEND Detects Early Improvements in Infants with SMA Type 1 but is not Sensitive to Continued Advances in Motor Function,” stressed the need to develop new assessment tools or adapt the CHOP-INTEND scale to accurately analyze motor abilities beyond those normally achieved in type 1 SMA children.

Another study, “VXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Continued Independence from Nutritional and Ventilatory Support in Patients Dosed Early in Disease Progression,” focused on nutritional and breathing support, which is typically required by type 1 SMA children by 12 months of age.

At the end of the study, 7 out of 10 patients remained free of ventilatory support, while 6 out of 7 remained free of nutritional support. Importantly, the number of patients able to feed by mouth increased from seven to 11, “suggesting the potential of AVXS-101 to improve swallowing function,” the researchers wrote.

“Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support,” the investigators said. They also observed that the data presented at the AAN meeting demonstrates patients’ continued independence.

After the 24-month follow-up in the Phase 1 trial, 11 patients have enrolled in a long-term follow-up trial (NCT03421977) for ongoing evaluation for up to 15 years. The oldest child receiving the therapeutic dose was 46.2 months old at the time of the last visit.

“The long-term follow-up data from the Phase 1 trial showed unprecedented event-free survival, continued developmental milestone achievement and long-term durability, with no new safety findings,” said Sukumar Nagendran, MD, chief medical officer of AveXis. “In aggregate, these data presented at AAN demonstrate a one-time administration of AVXS-101 appears to have a potentially clinically transformative and durable impact on patients with SMA Type 1.”